title: Deletion of Smad4 in fibroblasts leads to defective chondrocyte maturation and cartilage production in a TGFβ type II receptor independent manner.
abstract: The transforming growth factor β (TGFβ) superfamily growth factors play vital roles during the development, homeostasis, and pathogenesis of multi-cellular organisms. Smad4 serves as an exclusive co-activating smad that elicits most of the transcription responses invoked by the TGFβ superfamily members. We used Cre recombinase driven by the Fsp1/S100A4 promoter to delete the Smad4 gene in fibroblasts. We show that Fsp1/S100A4 is expressed in the elastic and fibrocartilage, and demonstrate that the fsp1-Cre; Smad4 flox/flox mutants have normal body size, but exhibit a short ear phenotype due to the deletion of the Smad4 gene in the ear chondrocytes. In contrast, TGFβ type II receptor deletion using Fsp1-cre does not lead to this phenotype, supporting the notion that non-TGFβ mediated signaling via Smad4 is essential for proper formation of ear cartilage during development. Smad4 deficiency in Fsp1(+) fibroblasts leads to defective chondrocyte maturation and cartilage production, likely due to a deficiency in bone morphogenic protein 5 (BMP-5) mediated signaling via Smad4. Our results emphasize the importance of BMP signaling pathways in the maturation and function of certain lineages of chondrocytes and offer an insight into the heterogeneity of the chondrocyte population in the body.
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Teng
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D055417:Bone Morphogenetic Protein 5 / Q000494:pharmacology; D002356:Cartilage / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000166:cytology* / Q000502:physiology; D004423:Ear / Q000002:abnormalities; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D055417:Bone Morphogenetic Protein 5; D018125:Receptors, Transforming Growth Factor beta; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II